Search

PurposeTraumatic brain injury (TBI) and potentially traumatic events (PTEs) contribute to increased substance use, mental health issues, and cognitive impairments. However, there's not enough research on how TBI and PTEs combined impact mental heath, substance use, and neurocognition.MethodsThis study leverages a subset of The National Consortium on Alcohol and Neurodevelopment in Adolescence (NCANDA) multi-site dataset with 551 adolescents to assess the combined and distinctive impacts of TBI, PTEs, and TBI+PTEs (prior to age 18) on substance use, mental health, and neurocognitive outcomes at age 18.ResultsTBI, PTEs, and TBI+PTEs predicted greater lifetime substance use and past-year alcohol and cannabis use. PTEs predicted greater internalizing symptoms, while TBI+PTEs predicted greater externalizing symptoms. Varying effects on neurocognitive outcomes included PTEs influencing attention accuracy and TBI+PTEs predicting faster speed in emotion tasks. PTEs predicted greater accuracy in abstraction-related tasks. Associations with working memory were not detected.ConclusionThis exploratory study contributes to the growing literature on the complex interplay between TBI, PTEs, and adolescent mental health, substance use, and neurocognition. The developmental implications of trauma via TBIs and/or PTEs during adolescence are considerable and worthy of further investigation.

Background and objectivesAmyloid pathology, vascular disease pathology, and pathologies affecting the medial temporal lobe are associated with cognitive trajectories in older adults. However, only limited evidence exists on how these pathologies influence cognition in the oldest old. We evaluated whether amyloid burden, white matter hyperintensity (WMH) volume, and hippocampal volume (HV) are associated with cognitive level and decline in the oldest old.MethodsThis was a longitudinal, observational community-based cohort study. We included participants with 18F-florbetapir PET and MRI data from the 90+ Study. Amyloid load was measured using the standardized uptake value ratio in the precuneus/posterior cingulate with eroded white matter mask as reference. WMH volume was log-transformed. All imaging measures were standardized using sample means and SDs. HV and log-WMH volume were normalized by total intracranial volume using the residual approach. Global cognitive performance was measured by the Mini-Mental State Examination (MMSE) and modified MMSE (3MS) tests, repeated every 6 months. We used linear mixed-effects models with random intercepts; random slopes; and interaction between time, time squared, and imaging variables to estimate the associations of imaging variables with cognitive level and cognitive decline. Models were adjusted for demographics, APOE genotype, and health behaviors.ResultsThe sample included 192 participants. The mean age was 92.9 years, 125 (65.1%) were female, 71 (37.0%) achieved a degree beyond college, and the median follow-up time was 3.0 years. A higher amyloid load was associated with a lower cognitive level (βMMSE = -0.82, 95% CI -1.17 to -0.46; β3MS = -2.77, 95% CI -3.69 to -1.84). A 1-SD decrease in HV was associated with a 0.70-point decrease in the MMSE score (95% CI -1.14 to -0.27) and a 2.27-point decrease in the 3MS score (95% CI -3.40 to -1.14). Clear nonlinear cognitive trajectories were detected. A higher amyloid burden and smaller HV were associated with faster cognitive decline. WMH volume was not significantly associated with cognitive level or decline.DiscussionAmyloid burden and hippocampal atrophy are associated with both cognitive level and cognitive decline in the oldest old. Our findings shed light on how different pathologies contributed to driving cognitive function in the oldest old.

IntroductionAlzheimer's disease (AD) pathology is defined by β-amyloid (Aβ) plaques and neurofibrillary tau, but Lewy bodies (LBs; ?-synuclein aggregates) are a common co-pathology for which effective biomarkers are needed.MethodsA validated α-synuclein Seed Amplification Assay (SAA) was used on recent cerebrospinal fluid (CSF) samples from 1638 Alzheimer's Disease Neuroimaging Initiative (ADNI) participants, 78 with LB-pathology confirmation at autopsy. We compared SAA outcomes with neuropathology, Aβ and tau biomarkers, risk-factors, genetics, and cognitive trajectories.ResultsSAA showed 79% sensitivity and 97% specificity for LB pathology, with superior performance in identifying neocortical (100%) compared to limbic (57%) and amygdala-predominant (60%) LB-pathology. SAA+ rate was 22%, increasing with disease stage and age. Higher Aβ burden but lower CSF p-tau181 associated with higher SAA+ rates, especially in dementia. SAA+ affected cognitive impairment in MCI and Early-AD who were already AD biomarker positive.DiscussionSAA is a sensitive, specific marker for LB-pathology. Its increase in prevalence with age and AD stages, and its association with AD biomarkers, highlights the clinical importance of α-synuclein co-pathology in understanding AD's nature and progression.HighlightsSAA shows 79% sensitivity, 97% specificity for LB-pathology detection in AD. SAA positivity prevalence increases with disease stage and age. Higher Aβ burden, lower CSF p-tau181 linked with higher SAA+ rates in dementia. SAA+ impacts cognitive impairment in early disease stages. Study underpins need for wider LB-pathology screening in AD treatment.

BackgroundCognitive impairment and dementia are frequently under-recognized. Health system strategies anchored in primary care are essential to address gaps in timely, comprehensive diagnosis. The goal of this paper is to describe the adaptation of a tablet-based brain health assessment (TabCAT-BHA) intervention and the study protocol to test its effectiveness in improving the detection of cognitive impairment, including dementia.MethodsThis mixed-methods, pragmatic, cluster randomized, hybrid effectiveness-implementation trial is being conducted in two 18-month waves with 26 Kaiser Permanente Southern California primary care clinics, with 13 serving as intervention clinics and 13 as usual care clinics. Patients 65 years and older with memory concerns (n ~ 180,000) receiving care at the 26 clinics will be included in the analyses. Primary care clinics are provided the following practice supports as part of the TabCAT-BHA intervention: brief education and training on neurocognitive disorders and study workflows; digital tools to assess cognitive function and support clinician decision making and documentation; and registered nurse support during the work-up and post-diagnosis periods for primary care providers, patients, and families. The intervention was adapted based on engagement with multiple levels of clinical and operational leaders in the healthcare system. Effectiveness outcomes include rates of cognitive impairment diagnosis in primary care and rates of completed standardized cognitive assessments and specialist referrals with incident diagnoses. Implementation outcomes include acceptability-appropriateness-feasibility, adoption, and fidelity.ResultsWe identified seven themes organized by system-, provider-, and patient-level domains that were used to adapt the TabCAT-BHA intervention. Accordingly, changes were made to the provider education, diagnostic work-up, and post-diagnostic support. Results will be reported in fall of 2027.ConclusionsOur engagement with multiple primary and specialty care clinical and operational leaders to adapt the TabCAT-BHA intervention to these primary care clinics has informed the protocol to evaluate the interventions effectiveness for improving the detection of cognitive impairment, including dementia, in an integrated healthcare system.Trial registationClinicaltrials.gov: NCT06090578 (registered 10/24/23).

This study investigates various pathological tau isoforms in the retina of individuals with early and advanced Alzheimers disease (AD), exploring their connection with disease status. Retinal cross-sections from predefined superior-temporal and inferior-temporal subregions and corresponding brains from neuropathologically confirmed AD patients with a clinical diagnosis of either mild cognitive impairment (MCI) or dementia (n = 45) were compared with retinas from age- and sex-matched individuals with normal cognition (n = 30) and non-AD dementia (n = 4). Retinal tau isoforms, including tau tangles, paired helical filament of tau (PHF-tau), oligomeric-tau (Oligo-tau), hyperphosphorylated-tau (p-tau), and citrullinated-tau (Cit-tau), were stereologically analyzed by immunohistochemistry and Nanostring GeoMx digital spatial profiling, and correlated with clinical and neuropathological outcomes. Our data indicated significant increases in various AD-related pretangle tau isoforms, especially p-tau (AT8, 2.9-fold, pS396-tau, 2.6-fold), Cit-tau at arginine residue 209 (CitR209-tau; 4.1-fold), and Oligo-tau (T22+, 9.2-fold), as well as pretangle and mature tau tangle forms like MC-1-positive (1.8-fold) and PHF-tau (2.3-fold), in AD compared to control retinas. MCI retinas also exhibited substantial increases in Oligo-tau (5.2-fold), CitR209-tau (3.5-fold), and pS396-tau (2.2-fold). Nanostring GeoMx analysis confirmed elevated retinal p-tau at epitopes: Ser214 (2.3-fold), Ser396 (2.6-fold), Ser404 (2.4-fold), and Thr231 (1.8-fold), particularly in MCI patients. Strong associations were found between retinal tau isoforms versus brain pathology and cognitive status: a) retinal Oligo-tau vs. Braak stage, neurofibrillary tangles (NFTs), and CDR cognitive scores (ρ = 0.63-0.71), b) retinal PHF-tau vs. neuropil threads (NTs) and ABC scores (ρ = 0.69-0.71), and c) retinal pS396-tau vs. NTs, NFTs, and ABC scores (ρ = 0.67-0.74). Notably, retinal Oligo-tau strongly correlated with retinal Aβ42 and arterial Aβ40 forms (r = 0.76-0.86). Overall, this study identifies and quantifies diverse retinal tau isoforms in MCI and AD patients, underscoring their link to brain pathology and cognition. These findings advocate for further exploration of retinal tauopathy biomarkers to facilitate AD detection and monitoring via noninvasive retinal imaging.

BACKGROUND: Amyloid beta protein (Aβ) is a treatment target in Alzheimers Disease (AD). Lowering production of its parent protein, APP, has benefits in preclinical models. Posiphen, an orally administered small molecule, binds to an iron-responsive element in APP mRNA and decreases translation of APP and Aβ. To augment human data for Posiphen, we evaluated safety, tolerability and pharmacokinetic and pharmacodynamic (PD) effects on Aβ metabolism using Stable Isotope Labeling Kinetic (SILK) analysis. METHODS: Double-blind phase 1b randomized ascending dose clinical trial, at five sites, under an IRB-approved protocol. Participants with mild cognitive impairment or mild AD (Early AD) confirmed by low CSF Aβ42/40 were randomized (within each dose arm) to Posiphen or placebo. Pretreatment assessment included lumbar puncture for CSF. Participants took Posiphen or placebo for 21-23 days, then underwent CSF catheter placement, intravenous infusion of 13C6-leucine, and CSF sampling for 36 h. Safety and tolerability were assessed through participant reports, EKG and laboratory tests. CSF SILK analysis measured Aβ40, 38 and 42 with immunoprecipitation-mass spectrometry. Baseline and day 21 CSF APP, Aβ and other biomarkers were measured with immunoassays. The Mini-Mental State Exam and ADAS-cog12 were given at baseline and day 21. RESULTS: From June 2017 to December 2021, 19 participants were enrolled, randomized within dose cohorts (5 active: 3 placebo) of 60 mg once/day and 60 mg twice/day; 1 participant was enrolled and completed 60 mg three times/day. 10 active drug and 5 placebo participants completed all study procedures. Posiphen was safe and well-tolerated. 8 participants had headaches related to CSF catheterization; 5 needed blood patches. Prespecified SILK analyses of Fractional Synthesis Rate (FSR) for CSF Aβ40 showed no significant overall or dose-dependent effects of Posiphen vs. placebo. Comprehensive multiparameter modeling of APP kinetics supported dose-dependent lowering of APP production by Posiphen. Cognitive measures and CSF biomarkers did not change significantly from baseline to 21 days in Posiphen vs. placebo groups. CONCLUSIONS: Posiphen was safe and well-tolerated in Early AD. A multicenter SILK study was feasible. Findings are limited by small sample size but provide additional supportive safety and PK data. Comprehensive modeling of biomarker dynamics using SILK data may reveal subtle drug effects. TRIAL REGISTRATION: NCT02925650 on clinicaltrials.gov (registered on 10-24-2016).

INTRODUCTION: The objective of this pilot study was to establish the feasibility of recruiting older Vietnamese Americans for research addressing genetic and nongenetic risk factors for Alzheimer disease (AD). METHODS: Twenty-six Vietnamese Americans were recruited from communities in San Diego. A Community Advisory Board provided cultural and linguistic advice. Bilingual/bicultural staff measured neuropsychological, neuropsychiatric, lifestyle, and medical/neurological functioning remotely. Saliva samples allowed DNA extraction. A consensus team reviewed clinical data to determine a diagnosis of normal control (NC), mild cognitive impairment (MCI), or dementia. Exploratory analyses addressed AD risk by measuring subjective cognitive complaints (SCC), depression, and vascular risk factors (VRFs). RESULTS: Twenty-five participants completed the study (mean age=73.8 y). Eighty percent chose to communicate in Vietnamese. Referrals came primarily from word of mouth within Vietnamese communities. Diagnoses included 18 NC, 3 MCI, and 4 dementia. Participants reporting SCC acknowledged more depressive symptoms and had greater objective cognitive difficulty than those without SCC. Eighty-eight percent of participants reported at least 1 VRF. DISCUSSION: This pilot study supports the feasibility of conducting community-based research in older Vietnamese Americans. Challenges included developing linguistically and culturally appropriate cognitive and neuropsychiatric assessment tools. Exploratory analyses addressing nongenetic AD risk factors suggest topics for future study.

BACKGROUND: Pathologic perivascular spaces (PVS), the fluid-filled compartments surrounding brain vasculature, may underlie cognitive decline in Parkinsons disease (PD). However, whether this impacts specific cognitive domains has not been investigated. OBJECTIVES: This study examined the relationship of PVS volume at baseline with domain-specific and global cognitive change over 2 years in PD individuals. METHODS: A total of 39 individuals with PD underwent 3T T1w magnetic resonance imaging to determine PVS volume fraction (PVS volume normalized to total regional volume) within (i) centrum semiovale, (ii) prefrontal white matter (medial orbitofrontal, rostral middle frontal, and superior frontal), and (iii) basal ganglia. A neuropsychological battery included assessment of cognitive domains and global cognitive function at baseline and after 2 years. RESULTS: Higher basal ganglia PVS at baseline was associated with greater decline in attention, executive function, and global cognition scores. CONCLUSIONS: While previous reports have associated elevated PVS volume in the basal ganglia with decline in global cognition in PD, our findings show such decline may affect the attention and executive function domains.

BACKGROUND: Midlife residential exposure to greenspace may slow cognitive decline by increasing opportunities for physical activity and social connection, restoring attention, or reducing stress or adverse environmental exposures. However, prospective studies on the association between greenness and cognitive decline are sparse. OBJECTIVE: We investigated the prospective association between greenness at midlife and cognitive decline later in life. We explored effect measure modification by apolipoprotein E (APOE)-ɛ4 carrier status, neighborhood socioeconomic status (NSES), and rural/urban regions. METHODS: The Nurses Health Study (N=121,700) started in 1976 with married female nurses, 30-55 years of age, located across 11 US states. We examined 16,962 nurses who were enrolled in a substudy starting in 1995-2001 (mean age=74y) through 2008. We assessed average summer residential greenness in a 270-m buffer using Landsat Normalized Difference Vegetation Index data from 1986-1994. Starting in 1995-2001, participants underwent up to four repeated measures of five cognitive tests. A global composite score was calculated as the average of all z-scores for each task to evaluate overall cognition. We used linear mixed models to evaluate the association of average greenness exposure at midlife with cognitive decline in later life, adjusted for age, education, NSES, and depression. RESULTS: In adjusted models, higher midlife greenness exposure [per interquartile range (IQR): 0.18] was associated with a 0.004-unit (95% CI: 0.001, 0.006) slower annual rate of cognitive decline. For comparison, we found that 1 year of age is related to a -0.006 mean annual difference for global cognition in the full sample; thus, higher midlife greenness appeared equivalent to slowing cognitive decline by ∼8 months. In analysis exploring gene-environment interactions, we found that among APOE-ɛ4 carriers, an IQR increase in greenness was associated with a rate of decline that was slower by 0.01 units of global composite score (95% CI: 0.0004, 0.02). This association was attenuated among APOE-ɛ4 noncarriers. We did not observe associations between greenness and baseline or annual rate of cognitive decline of verbal memory. DISCUSSION: Higher midlife greenness exposure is associated with slower cognitive decline later in life. Future research is necessary to confirm these findings. https://doi.org/10.1289/EHP13588.

ObjectiveHispanic/Latino individuals in the U.S. have the highest prevalence of undiagnosed and untreated diabetes and are at increased risk for cognitive impairment. In this study, we examine glycemic control in relation to cognitive aging and impairment in a large prospective cohort of middle-aged and older Hispanic/Latino individuals of diverse heritages.Research design and methodsStudy of Latinos-Investigation of Neurocognitive Aging (SOL-INCA) is a Hispanic Community Health Study/Study of Latinos (HCHS/SOL) ancillary study. HCHS/SOL is a multisite (Bronx, NY; Chicago, IL; Miami, FL; and San Diego, CA), probability sampled prospective cohort study. SOL-INCA enrolled 6,377 diverse Hispanic/Latino individuals aged 50 years and older (2016-2018). The primary outcomes were cognitive function, 7-year cognitive decline, and mild cognitive impairment (MCI). The primary glycemia exposure variables were measured from fasting blood samples collected at HCHS/SOL visit 1 (2008-2011).ResultsVisit 1 mean age was 56.5 years ± 8.2 SD, and the average glycosylated hemoglobin A1C (HbA1c) was 6.12% (43.5 ± 14.6 mmol/mol). After covariate adjustment, higher HbA1c was associated with accelerated 7-year global (b = -0.045; 95% CI -0.070; -0.021; in z score units) and executive cognitive decline and a higher prevalence of MCI (odds ratio 1.20; 95% CI 1.11; 1.29).ConclusionsElevated HbA1c levels were associated with 7-year executive cognitive decline and increased MCI risk among diverse middle-aged and older Hispanic/Latino individuals. Our findings indicate that poor glycemic control in midlife may pose significant risks for cognitive decline and MCI later in life among Hispanic/Latino individuals of diverse heritages.

Purpose of reviewCannabis may have beneficial anti-inflammatory effects in people with HIV (PWH); however, given this population's high burden of persisting neurocognitive impairment (NCI), clinicians are concerned they may be particularly vulnerable to the deleterious effects of cannabis on cognition. Here, we present a systematic scoping review of clinical and preclinical studies evaluating the effects of cannabinoid exposure on cognition in HIV.Recent findingsResults revealed little evidence to support a harmful impact of cannabis use on cognition in HIV, with few eligible preclinical data existing. Furthermore, the beneficial/harmful effects of cannabis use observed on cognition were function-dependent and confounded by several factors (e.g., age, frequency of use). Results are discussed alongside potential mechanisms of cannabis effects on cognition in HIV (e.g., anti-inflammatory), and considerations are outlined for screening PWH that may benefit from cannabis interventions. We further highlight the value of accelerating research discoveries in this area by utilizing translatable cross-species tasks to facilitate comparisons across human and animal work.

Based on emerging evidence on the role for specific single-nucleotide variants (SNVs) in EIF2AK3 encoding the integrated stress response kinase PERK, in neurodegeneration, we assessed the association of EIF2AK3 SNVs with neurocognitive performance in people with HIV (PWH) using a candidate gene approach. This retrospective study included the CHARTER cohort participants, excluding those with severe neuropsychiatric comorbidities. Genome-wide data previously obtained for 1047 participants and targeted sequencing of 992 participants with available genomic DNA were utilized to interrogate the association of three noncoding and three coding EIF2AK3 SNVs with the continuous global deficit score (GDS) and global neurocognitive impairment (NCI; GDS ≥ 0.5) using univariable and multivariable methods, with demographic, disease-associated, and treatment characteristics as covariates. The cohort characteristics were as follows: median age, 43.1 years; females, 22.8%; European ancestry, 41%; median CD4 + T cell counts, 175/µL (nadir) and 428/µL (current). At first assessment, 70.5% used ART and 68.3% of these had plasma HIV RNA levels ≤ 200 copies/mL. All three noncoding EIF2AK3 SNVs were associated with GDS and NCI (all p  13 were independently associated with GDS and NCI (p

Cancer-related cognitive impairment (CRCI) is a consequence of chemotherapy and extracranial radiation therapy (ECRT). Our prior work demonstrated gliosis in the brain following ECRT in SKH1 mice. The signals that induce gliosis were unclear. Right hindlimb skin from SKH1 mice was treated with 20 Gy or 30 Gy to induce subclinical or clinical dermatitis, respectively. Mice were euthanized at 6 h, 24 h, 5 days, 12 days, and 25 days post irradiation, and the brain, thoracic spinal cord, and skin were collected. The brains were harvested for spatial proteomics, immunohistochemistry, Nanostring nCounter® glial profiling, and neuroinflammation gene panels. The thoracic spinal cords were evaluated by immunohistochemistry. Radiation injury to the skin was evaluated by histology. The genes associated with neurotransmission, glial cell activation, innate immune signaling, cell signal transduction, and cancer were differentially expressed in the brains from mice treated with ECRT compared to the controls. Dose-dependent increases in neuroinflammatory-associated and neurodegenerative-disease-associated proteins were measured in the brains from ECRT-treated mice. Histologic changes in the ECRT-treated mice included acute dermatitis within the irradiated skin of the hindlimb and astrocyte activation within the thoracic spinal cord. Collectively, these findings highlight indirect neuronal transmission and glial cell activation in the pathogenesis of ECRT-related CRCI, providing possible signaling pathways for mitigation strategies.

IntroductionData-driven neuropsychological methods can identify mild cognitive impairment (MCI) subtypes with stronger associations to dementia risk factors than conventional diagnostic methods.MethodsCluster analysis used neuropsychological data from participants without dementia (mean age = 71.6 years) in the National Alzheimer's Coordinating Center (NACC) Uniform Data Set (n = 26,255) and the "normal cognition" subsample (n = 16,005). Survival analyses examined MCI or dementia progression.ResultsFive clusters were identified: "Optimal" cognitively normal (oCN; 13.2%), "Typical" CN (tCN; 28.0%), Amnestic MCI (aMCI; 25.3%), Mixed MCI-Mild (mMCI-Mild; 20.4%), and Mixed MCI-Severe (mMCI-Severe; 13.0%). Progression to dementia differed across clusters (oCN

IntroductionDepressive symptoms are associated with higher risk of dementia, but how they impact cognition in diverse populations is unclear.MethodsAsian, Black, Latino, or White participants (n = 2227) in the Kaiser Healthy Aging and Diverse Life Experiences (age 65+) and the Study of Healthy Aging in African Americans (age 50+) underwent up to three waves of cognitive assessments over 4 years. Multilevel models stratified by race/ethnicity were used to examine whether depressive symptoms were associated with cognition or cognitive decline and whether associations differed by race/ethnicity.ResultsHigher depressive symptoms were associated with lower baseline verbal episodic memory scores (-0.06, 95% CI: -0.12, -0.01; -0.15, 95% CI: -0.25, -0.04), and faster decline annually in semantic memory (-0.04, 95% CI: -0.07, -0.01; -0.10, 95% CI: -0.15, -0.05) for Black and Latino participants. Depressive symptoms were associated with lower baseline but not decline in executive function.DiscussionDepressive symptoms were associated with worse cognitive outcomes, with some evidence of heterogeneity across racial/ethnic groups.HighlightsWe examined whether baseline depressive symptoms were differentially associated with domain-specific cognition or cognitive decline by race/ethnicity. Depressive symptoms were associated with worse cognitive scores for all racial/ethnic groups across different domains examined. Higher depressive symptoms were associated with faster cognitive decline for semantic memory for Black and Latino participants. The results suggest a particularly harmful association between depressive symptoms and cognition in certain racial/ethnic groups.